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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial</title>
<author><name sortKey="Stark, Dan" sort="Stark, Dan" uniqKey="Stark D" first="Dan" last="Stark">Dan Stark</name>
<affiliation><nlm:aff id="aff1">Leeds Institute of Molecular Medicine, University of Leeds, St James's Institute of Oncology, Leeds, UK</nlm:aff>
</affiliation><author><name sortKey="Nankivell, Matthew" sort="Nankivell, Matthew" uniqKey="Nankivell M" first="Matthew" last="Nankivell">Matthew Nankivell</name>
<affiliation><nlm:aff id="aff2">Medical Research Council Clinical Trials Unit, London, UK</nlm:aff>
</affiliation><author><name sortKey="Pujade Lauraine, Eric" sort="Pujade Lauraine, Eric" uniqKey="Pujade Lauraine E" first="Eric" last="Pujade-Lauraine">Eric Pujade-Lauraine</name>
<affiliation><nlm:aff id="aff3">Université Paris Descartes, AP-HP, Hôpitaux Universitaires Paris Centre, Hôtel-Dieu, Paris, France</nlm:aff>
</affiliation><author><name sortKey="Kristensen, Gunnar" sort="Kristensen, Gunnar" uniqKey="Kristensen G" first="Gunnar" last="Kristensen">Gunnar Kristensen</name>
<affiliation><nlm:aff id="aff4">Department of Gynecologic Oncology and Institute of Medical Informatics, Oslo University Hospital, Oslo, Norway</nlm:aff>
</affiliation><author><name sortKey="Elit, Lorraine" sort="Elit, Lorraine" uniqKey="Elit L" first="Lorraine" last="Elit">Lorraine Elit</name>
<affiliation><nlm:aff id="aff5">Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada</nlm:aff>
</affiliation><author><name sortKey="Stockler, Martin" sort="Stockler, Martin" uniqKey="Stockler M" first="Martin" last="Stockler">Martin Stockler</name>
<affiliation><nlm:aff id="aff6">Australia New Zealand Gynaecological Oncology Group, University of Sydney, Camperdown, NSW, Australia</nlm:aff>
</affiliation><affiliation><nlm:aff id="aff7">National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia</nlm:aff>
</affiliation><author><name sortKey="Hilpert, Felix" sort="Hilpert, Felix" uniqKey="Hilpert F" first="Felix" last="Hilpert">Felix Hilpert</name>
<affiliation><nlm:aff id="aff8">Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Kiel, Germany</nlm:aff>
</affiliation><author><name sortKey="Cervantes, Andres" sort="Cervantes, Andres" uniqKey="Cervantes A" first="Andrés" last="Cervantes">Andrés Cervantes</name>
<affiliation><nlm:aff id="aff9">Department of Hematology and Medical Oncology, Institute of Health Research Hospital Clinico, University of Valencia, Valencia, Spain</nlm:aff>
</affiliation><author><name sortKey="Brown, Julia" sort="Brown, Julia" uniqKey="Brown J" first="Julia" last="Brown">Julia Brown</name>
<affiliation><nlm:aff id="aff1">Leeds Institute of Molecular Medicine, University of Leeds, St James's Institute of Oncology, Leeds, UK</nlm:aff>
</affiliation><author><name sortKey="Lanceley, Anne" sort="Lanceley, Anne" uniqKey="Lanceley A" first="Anne" last="Lanceley">Anne Lanceley</name>
<affiliation><nlm:aff id="aff10">Department of Women's Cancer, Institute for Women's Health, University College London, London, UK</nlm:aff>
</affiliation><author><name sortKey="Velikova, Galina" sort="Velikova, Galina" uniqKey="Velikova G" first="Galina" last="Velikova">Galina Velikova</name>
<affiliation><nlm:aff id="aff1">Leeds Institute of Molecular Medicine, University of Leeds, St James's Institute of Oncology, Leeds, UK</nlm:aff>
</affiliation><author><name sortKey="Sabate, Eduardo" sort="Sabate, Eduardo" uniqKey="Sabate E" first="Eduardo" last="Sabate">Eduardo Sabate</name>
<affiliation><nlm:aff id="aff11">F Hoffmann-La Roche, Basel, Switzerland</nlm:aff>
</affiliation><author><name sortKey="Pfisterer, Jacobus" sort="Pfisterer, Jacobus" uniqKey="Pfisterer J" first="Jacobus" last="Pfisterer">Jacobus Pfisterer</name>
<affiliation><nlm:aff id="aff12">Städtisches Klinikum Solingen, Klinik für Gynäkologie und Geburtshilfe, Solingen, Germany</nlm:aff>
</affiliation><author><name sortKey="Carey, Mark S" sort="Carey, Mark S" uniqKey="Carey M" first="Mark S" last="Carey">Mark S. Carey</name>
<affiliation><nlm:aff id="aff13">Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada</nlm:aff>
</affiliation><author><name sortKey="Beale, Philip" sort="Beale, Philip" uniqKey="Beale P" first="Philip" last="Beale">Philip Beale</name>
<affiliation><nlm:aff id="aff6">Australia New Zealand Gynaecological Oncology Group, University of Sydney, Camperdown, NSW, Australia</nlm:aff>
</affiliation><author><name sortKey="Qian, Wendi" sort="Qian, Wendi" uniqKey="Qian W" first="Wendi" last="Qian">Wendi Qian</name>
<affiliation><nlm:aff id="aff14">Cambridge Cancer Trials Centre, Cambridge, UK</nlm:aff>
</affiliation><author><name sortKey="Swart, Ann Marie" sort="Swart, Ann Marie" uniqKey="Swart A" first="Ann Marie" last="Swart">Ann Marie Swart</name>
<affiliation><nlm:aff id="aff2">Medical Research Council Clinical Trials Unit, London, UK</nlm:aff>
</affiliation><author><name sortKey="Oza, Amit" sort="Oza, Amit" uniqKey="Oza A" first="Amit" last="Oza">Amit Oza</name>
<affiliation><nlm:aff id="aff15">Princess Margaret Hospital, Toronto, ON, Canada</nlm:aff>
</affiliation><author><name sortKey="Perren, Tim" sort="Perren, Tim" uniqKey="Perren T" first="Tim" last="Perren">Tim Perren</name>
<affiliation><nlm:aff id="aff16">St James's Institute of Oncology, St James's University Hospital, Leeds, UK</nlm:aff>
</affiliation><publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">23333117</idno>
<idno type="pmc">3596061</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596061</idno>
<idno type="RBID">PMC:3596061</idno>
<idno type="doi">10.1016/S1470-2045(12)70567-3</idno>
<date when="2013">2013</date>
<idno type="wicri:Area/Pmc/Corpus">002725</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002725</idno>
</publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial</title>
<author><name sortKey="Stark, Dan" sort="Stark, Dan" uniqKey="Stark D" first="Dan" last="Stark">Dan Stark</name>
<affiliation><nlm:aff id="aff1">Leeds Institute of Molecular Medicine, University of Leeds, St James's Institute of Oncology, Leeds, UK</nlm:aff>
</affiliation><author><name sortKey="Nankivell, Matthew" sort="Nankivell, Matthew" uniqKey="Nankivell M" first="Matthew" last="Nankivell">Matthew Nankivell</name>
<affiliation><nlm:aff id="aff2">Medical Research Council Clinical Trials Unit, London, UK</nlm:aff>
</affiliation><author><name sortKey="Pujade Lauraine, Eric" sort="Pujade Lauraine, Eric" uniqKey="Pujade Lauraine E" first="Eric" last="Pujade-Lauraine">Eric Pujade-Lauraine</name>
<affiliation><nlm:aff id="aff3">Université Paris Descartes, AP-HP, Hôpitaux Universitaires Paris Centre, Hôtel-Dieu, Paris, France</nlm:aff>
</affiliation><author><name sortKey="Kristensen, Gunnar" sort="Kristensen, Gunnar" uniqKey="Kristensen G" first="Gunnar" last="Kristensen">Gunnar Kristensen</name>
<affiliation><nlm:aff id="aff4">Department of Gynecologic Oncology and Institute of Medical Informatics, Oslo University Hospital, Oslo, Norway</nlm:aff>
</affiliation><author><name sortKey="Elit, Lorraine" sort="Elit, Lorraine" uniqKey="Elit L" first="Lorraine" last="Elit">Lorraine Elit</name>
<affiliation><nlm:aff id="aff5">Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada</nlm:aff>
</affiliation><author><name sortKey="Stockler, Martin" sort="Stockler, Martin" uniqKey="Stockler M" first="Martin" last="Stockler">Martin Stockler</name>
<affiliation><nlm:aff id="aff6">Australia New Zealand Gynaecological Oncology Group, University of Sydney, Camperdown, NSW, Australia</nlm:aff>
</affiliation><affiliation><nlm:aff id="aff7">National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia</nlm:aff>
</affiliation><author><name sortKey="Hilpert, Felix" sort="Hilpert, Felix" uniqKey="Hilpert F" first="Felix" last="Hilpert">Felix Hilpert</name>
<affiliation><nlm:aff id="aff8">Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Kiel, Germany</nlm:aff>
</affiliation><author><name sortKey="Cervantes, Andres" sort="Cervantes, Andres" uniqKey="Cervantes A" first="Andrés" last="Cervantes">Andrés Cervantes</name>
<affiliation><nlm:aff id="aff9">Department of Hematology and Medical Oncology, Institute of Health Research Hospital Clinico, University of Valencia, Valencia, Spain</nlm:aff>
</affiliation><author><name sortKey="Brown, Julia" sort="Brown, Julia" uniqKey="Brown J" first="Julia" last="Brown">Julia Brown</name>
<affiliation><nlm:aff id="aff1">Leeds Institute of Molecular Medicine, University of Leeds, St James's Institute of Oncology, Leeds, UK</nlm:aff>
</affiliation><author><name sortKey="Lanceley, Anne" sort="Lanceley, Anne" uniqKey="Lanceley A" first="Anne" last="Lanceley">Anne Lanceley</name>
<affiliation><nlm:aff id="aff10">Department of Women's Cancer, Institute for Women's Health, University College London, London, UK</nlm:aff>
</affiliation><author><name sortKey="Velikova, Galina" sort="Velikova, Galina" uniqKey="Velikova G" first="Galina" last="Velikova">Galina Velikova</name>
<affiliation><nlm:aff id="aff1">Leeds Institute of Molecular Medicine, University of Leeds, St James's Institute of Oncology, Leeds, UK</nlm:aff>
</affiliation><author><name sortKey="Sabate, Eduardo" sort="Sabate, Eduardo" uniqKey="Sabate E" first="Eduardo" last="Sabate">Eduardo Sabate</name>
<affiliation><nlm:aff id="aff11">F Hoffmann-La Roche, Basel, Switzerland</nlm:aff>
</affiliation><author><name sortKey="Pfisterer, Jacobus" sort="Pfisterer, Jacobus" uniqKey="Pfisterer J" first="Jacobus" last="Pfisterer">Jacobus Pfisterer</name>
<affiliation><nlm:aff id="aff12">Städtisches Klinikum Solingen, Klinik für Gynäkologie und Geburtshilfe, Solingen, Germany</nlm:aff>
</affiliation><author><name sortKey="Carey, Mark S" sort="Carey, Mark S" uniqKey="Carey M" first="Mark S" last="Carey">Mark S. Carey</name>
<affiliation><nlm:aff id="aff13">Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada</nlm:aff>
</affiliation><author><name sortKey="Beale, Philip" sort="Beale, Philip" uniqKey="Beale P" first="Philip" last="Beale">Philip Beale</name>
<affiliation><nlm:aff id="aff6">Australia New Zealand Gynaecological Oncology Group, University of Sydney, Camperdown, NSW, Australia</nlm:aff>
</affiliation><author><name sortKey="Qian, Wendi" sort="Qian, Wendi" uniqKey="Qian W" first="Wendi" last="Qian">Wendi Qian</name>
<affiliation><nlm:aff id="aff14">Cambridge Cancer Trials Centre, Cambridge, UK</nlm:aff>
</affiliation><author><name sortKey="Swart, Ann Marie" sort="Swart, Ann Marie" uniqKey="Swart A" first="Ann Marie" last="Swart">Ann Marie Swart</name>
<affiliation><nlm:aff id="aff2">Medical Research Council Clinical Trials Unit, London, UK</nlm:aff>
</affiliation><author><name sortKey="Oza, Amit" sort="Oza, Amit" uniqKey="Oza A" first="Amit" last="Oza">Amit Oza</name>
<affiliation><nlm:aff id="aff15">Princess Margaret Hospital, Toronto, ON, Canada</nlm:aff>
</affiliation><author><name sortKey="Perren, Tim" sort="Perren, Tim" uniqKey="Perren T" first="Tim" last="Perren">Tim Perren</name>
<affiliation><nlm:aff id="aff16">St James's Institute of Oncology, St James's University Hospital, Leeds, UK</nlm:aff>
</affiliation><series><title level="j">The Lancet Oncology</title>
<idno type="ISSN">1470-2045</idno>
<idno type="eISSN">1474-5488</idno>
<imprint><date when="2013">2013</date>
</imprint><profileDesc><textClass></textClass>
</profileDesc><front><div type="abstract" xml:lang="en"><title>Summary</title>
<sec><title>Background</title>
<p>In the Gynecologic Cancer Intergroup International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, bevacizumab improved progression-free survival in patients with ovarian cancer when used in combination with first-line chemotherapy and as a single-drug continuation treatment for 18 cycles. In a preliminary analysis of a high-risk subset of patients, there was also an improvement in overall survival. This study aims to describe the health-related quality-of-life (QoL) outcomes from ICON7.</p>
</sec><sec><title>Methods</title>
<p>ICON7 is a randomised, multicentre, open-label phase 3 trial. Between Dec 18, 2006, and Feb 16, 2009, after a surgical procedure aiming to debulk the disease, women with International Federation of Gynecology and Obstetrics (FIGO) high-risk stage I–IV epithelial ovarian cancer were randomly allocated (1:1) by computer program and block randomisation to receive either six cycles of standard chemotherapy (total 18 weeks) with carboplatin (area under the curve 5 or 6) and paclitaxel (175 mg/m<sup>2</sup>
) alone or with bevacizumab (7·5 mg/kg) given intravenously with chemotherapy and continued as a single drug thereafter (total 54 weeks). The primary QoL endpoint was global QoL from the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire–core 30 at week 54, analysed by ANOVA and adjusted for baseline score. Analyses were by intention to treat. The ICON7 trial has completed recruitment and remains in follow-up. This study is registered, number ISRCTN91273375.</p><sec><title>Findings</title>
<p>764 women were randomly assigned to the standard chemotherapy group and 764 to the bevacizumab group. At baseline, 684 (90%) of women in the standard chemotherapy group and 691 (90%) of those in the bevacizumab group had completed QoL questionnaires. At week 54, 502 (66%) women in the bevacizumab group and 388 (51%) women in the standard chemotherapy group provided QoL data. Overall, the mean global QoL score improved during chemotherapy by 7·2 points (SD 24·4) when analysed for all women with data at baseline and week 18. The mean global QoL score at 54 weeks was higher in the standard chemotherapy group than in the bevacizumab group (76·1 [SD 18·2] <italic>vs</italic>
69·7 [19·1] points; difference 6·4 points, 95% CI 3·7–9·0, p<0·0001).</p><sec><title>Interpretation</title>
<p>Bevacizumab continuation treatment seems to be associated with a small but clinically significant decrement in QoL compared with standard treatment for women with ovarian cancer. The trade-off between the prolongation of progression-free survival and the quality of that period of time needs to be considered in clinical practice when making treatment decisions.</p>
</sec><sec><title>Funding</title>
<p>Roche and the National Institute for Health Research through the UK National Cancer Research Network.</p>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Lancet Oncol</journal-id>
<journal-id journal-id-type="iso-abbrev">Lancet Oncol</journal-id>
<journal-title-group><journal-title>The Lancet Oncology</journal-title>
</journal-title-group><issn pub-type="ppub">1470-2045</issn>
<issn pub-type="epub">1474-5488</issn>
<publisher><publisher-name>Lancet Pub. Group</publisher-name>
</publisher><article-meta><article-id pub-id-type="pmid">23333117</article-id>
<article-id pub-id-type="pmc">3596061</article-id>
<article-id pub-id-type="publisher-id">LANONC70567</article-id>
<article-id pub-id-type="doi">10.1016/S1470-2045(12)70567-3</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Articles</subject>
</subj-group><title-group><article-title>Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial</article-title>
</title-group><contrib-group><contrib contrib-type="author"><name><surname>Stark</surname>
<given-names>Dan</given-names>
</name><email>d.p.stark@leeds.ac.uk</email>
<xref rid="aff1" ref-type="aff">a</xref>
<xref rid="cor1" ref-type="corresp">*</xref>
</contrib><contrib contrib-type="author"><name><surname>Nankivell</surname>
<given-names>Matthew</given-names>
</name><xref rid="aff2" ref-type="aff">b</xref>
</contrib><contrib contrib-type="author"><name><surname>Pujade-Lauraine</surname>
<given-names>Eric</given-names>
</name><xref rid="aff3" ref-type="aff">c</xref>
</contrib><contrib contrib-type="author"><name><surname>Kristensen</surname>
<given-names>Gunnar</given-names>
</name><xref rid="aff4" ref-type="aff">d</xref>
</contrib><contrib contrib-type="author"><name><surname>Elit</surname>
<given-names>Lorraine</given-names>
</name><xref rid="aff5" ref-type="aff">e</xref>
</contrib><contrib contrib-type="author"><name><surname>Stockler</surname>
<given-names>Martin</given-names>
</name><xref rid="aff6" ref-type="aff">f</xref>
<xref rid="aff7" ref-type="aff">g</xref>
</contrib><contrib contrib-type="author"><name><surname>Hilpert</surname>
<given-names>Felix</given-names>
</name><xref rid="aff8" ref-type="aff">h</xref>
</contrib><contrib contrib-type="author"><name><surname>Cervantes</surname>
<given-names>Andrés</given-names>
</name><xref rid="aff9" ref-type="aff">i</xref>
</contrib><contrib contrib-type="author"><name><surname>Brown</surname>
<given-names>Julia</given-names>
</name><xref rid="aff1" ref-type="aff">a</xref>
</contrib><contrib contrib-type="author"><name><surname>Lanceley</surname>
<given-names>Anne</given-names>
</name><xref rid="aff10" ref-type="aff">j</xref>
</contrib><contrib contrib-type="author"><name><surname>Velikova</surname>
<given-names>Galina</given-names>
</name><xref rid="aff1" ref-type="aff">a</xref>
</contrib><contrib contrib-type="author"><name><surname>Sabate</surname>
<given-names>Eduardo</given-names>
</name><xref rid="aff11" ref-type="aff">k</xref>
</contrib><contrib contrib-type="author"><name><surname>Pfisterer</surname>
<given-names>Jacobus</given-names>
</name><xref rid="aff12" ref-type="aff">l</xref>
</contrib><contrib contrib-type="author"><name><surname>Carey</surname>
<given-names>Mark S</given-names>
</name><xref rid="aff13" ref-type="aff">m</xref>
</contrib><contrib contrib-type="author"><name><surname>Beale</surname>
<given-names>Philip</given-names>
</name><xref rid="aff6" ref-type="aff">f</xref>
</contrib><contrib contrib-type="author"><name><surname>Qian</surname>
<given-names>Wendi</given-names>
</name><xref rid="aff14" ref-type="aff">n</xref>
</contrib><contrib contrib-type="author"><name><surname>Swart</surname>
<given-names>Ann Marie</given-names>
</name><xref rid="aff2" ref-type="aff">b</xref>
</contrib><contrib contrib-type="author"><name><surname>Oza</surname>
<given-names>Amit</given-names>
</name><xref rid="aff15" ref-type="aff">o</xref>
</contrib><contrib contrib-type="author"><name><surname>Perren</surname>
<given-names>Tim</given-names>
</name><xref rid="aff16" ref-type="aff">p</xref>
</contrib><aff id="aff1"><label>a</label>
Leeds Institute of Molecular Medicine, University of Leeds, St James's Institute of Oncology, Leeds, UK</aff><aff id="aff2"><label>b</label>
Medical Research Council Clinical Trials Unit, London, UK</aff><aff id="aff3"><label>c</label>
Université Paris Descartes, AP-HP, Hôpitaux Universitaires Paris Centre, Hôtel-Dieu, Paris, France</aff><aff id="aff4"><label>d</label>
Department of Gynecologic Oncology and Institute of Medical Informatics, Oslo University Hospital, Oslo, Norway</aff><aff id="aff5"><label>e</label>
Department of Obstetrics and Gynecology, McMaster University, Hamilton, ON, Canada</aff><aff id="aff6"><label>f</label>
Australia New Zealand Gynaecological Oncology Group, University of Sydney, Camperdown, NSW, Australia</aff><aff id="aff7"><label>g</label>
National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia</aff><aff id="aff8"><label>h</label>
Department of Gynecology and Obstetrics, University of Schleswig-Holstein, Kiel, Germany</aff><aff id="aff9"><label>i</label>
Department of Hematology and Medical Oncology, Institute of Health Research Hospital Clinico, University of Valencia, Valencia, Spain</aff><aff id="aff10"><label>j</label>
Department of Women's Cancer, Institute for Women's Health, University College London, London, UK</aff><aff id="aff11"><label>k</label>
F Hoffmann-La Roche, Basel, Switzerland</aff><aff id="aff12"><label>l</label>
Städtisches Klinikum Solingen, Klinik für Gynäkologie und Geburtshilfe, Solingen, Germany</aff><aff id="aff13"><label>m</label>
Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada</aff><aff id="aff14"><label>n</label>
Cambridge Cancer Trials Centre, Cambridge, UK</aff><aff id="aff15"><label>o</label>
Princess Margaret Hospital, Toronto, ON, Canada</aff><aff id="aff16"><label>p</label>
St James's Institute of Oncology, St James's University Hospital, Leeds, UK</aff><author-notes><corresp id="cor1"><label>*</label>
Correspondence to: Dr Dan Stark, Leeds Institute of Molecular Medicine, Level 4 Bexley Wing, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK <email>d.p.stark@leeds.ac.uk</email>
</corresp><pub-date pub-type="pmc-release"><day>1</day>
<month>3</month>
<year>2013</year>
</pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment><pub-date pub-type="ppub"><month>3</month>
<year>2013</year>
</pub-date><volume>14</volume>
<issue>3</issue>
<fpage>236</fpage>
<lpage>243</lpage>
<permissions><copyright-statement>© 2013 Elsevier Ltd. All rights reserved.</copyright-statement>
<copyright-year>2013</copyright-year>
<copyright-holder>Elsevier Ltd</copyright-holder>
<license><license-p>This document may be redistributed and reused, subject to <ext-link ext-link-type="uri" xlink:href="http://www.elsevier.com/wps/find/authorsview.authors/supplementalterms1.0">certain conditions</ext-link>
.</license-p><abstract><title>Summary</title>
<sec><title>Background</title>
<p>In the Gynecologic Cancer Intergroup International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, bevacizumab improved progression-free survival in patients with ovarian cancer when used in combination with first-line chemotherapy and as a single-drug continuation treatment for 18 cycles. In a preliminary analysis of a high-risk subset of patients, there was also an improvement in overall survival. This study aims to describe the health-related quality-of-life (QoL) outcomes from ICON7.</p>
</sec><sec><title>Methods</title>
<p>ICON7 is a randomised, multicentre, open-label phase 3 trial. Between Dec 18, 2006, and Feb 16, 2009, after a surgical procedure aiming to debulk the disease, women with International Federation of Gynecology and Obstetrics (FIGO) high-risk stage I–IV epithelial ovarian cancer were randomly allocated (1:1) by computer program and block randomisation to receive either six cycles of standard chemotherapy (total 18 weeks) with carboplatin (area under the curve 5 or 6) and paclitaxel (175 mg/m<sup>2</sup>
) alone or with bevacizumab (7·5 mg/kg) given intravenously with chemotherapy and continued as a single drug thereafter (total 54 weeks). The primary QoL endpoint was global QoL from the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire–core 30 at week 54, analysed by ANOVA and adjusted for baseline score. Analyses were by intention to treat. The ICON7 trial has completed recruitment and remains in follow-up. This study is registered, number ISRCTN91273375.</p><sec><title>Findings</title>
<p>764 women were randomly assigned to the standard chemotherapy group and 764 to the bevacizumab group. At baseline, 684 (90%) of women in the standard chemotherapy group and 691 (90%) of those in the bevacizumab group had completed QoL questionnaires. At week 54, 502 (66%) women in the bevacizumab group and 388 (51%) women in the standard chemotherapy group provided QoL data. Overall, the mean global QoL score improved during chemotherapy by 7·2 points (SD 24·4) when analysed for all women with data at baseline and week 18. The mean global QoL score at 54 weeks was higher in the standard chemotherapy group than in the bevacizumab group (76·1 [SD 18·2] <italic>vs</italic>
69·7 [19·1] points; difference 6·4 points, 95% CI 3·7–9·0, p<0·0001).</p><sec><title>Interpretation</title>
<p>Bevacizumab continuation treatment seems to be associated with a small but clinically significant decrement in QoL compared with standard treatment for women with ovarian cancer. The trade-off between the prolongation of progression-free survival and the quality of that period of time needs to be considered in clinical practice when making treatment decisions.</p>
</sec><sec><title>Funding</title>
<p>Roche and the National Institute for Health Research through the UK National Cancer Research Network.</p>
</sec><body><sec id="cesec10"><title>Introduction</title>
<p>Angiogenesis is central to the process of cancer growth and metastasis and has a role in the progression and prognosis of ovarian cancer.<xref rid="bib1 bib2" ref-type="bibr"><sup>1,2</sup>
</xref><xref rid="bib3" ref-type="bibr"><sup>3</sup>
</xref><xref rid="bib4" ref-type="bibr"><sup>4</sup>
</xref><p>The evaluation of treatments that achieve such gains in survival needs to include a comprehensive understanding of the other effects of these treatments on patients. Detailed health-related QoL assessment can provide a distinct and broad evaluation of the health, function, and wellbeing of people with cancer and of the functional and symptomatic benefits and losses that might result from the medical interventions. QoL is important in advanced ovarian cancer, where treatments can be effective but are only rarely curative.<xref rid="bib5" ref-type="bibr"><sup>5</sup>
</xref><xref rid="bib6 bib7 bib8" ref-type="bibr"><sup>6–8</sup>
</xref><xref rid="bib9 bib10 bib11" ref-type="bibr"><sup>9–11</sup>
</xref><xref rid="bib12 bib13" ref-type="bibr"><sup>12,13</sup>
</xref><sec sec-type="methods" id="cesec20"><title>Methods</title>
<sec id="cesec30"><title>Study design</title>
<p>ICON7 is a randomised, multicentre, open-label phase 3 trial designed to assess the safety and efficacy of adding intravenous bevacizumab (7·5 mg/kg, intravenous over 30–90 min on day 1 of every 3-week cycle; F Hoffmann-La Roche, Basel, Switzerland) to standard intravenous chemotherapy with carboplatin (area under the curve 5 or 6 intravenous over 1 h on day 1 of every 3-week cycle) and paclitaxel (175 mg/m<sup>2</sup>
, intravenous over 3 h on day 1 of every 3-week cycle) in the management of patients with FIGO high-risk stage I–IV epithelial ovarian cancer (<xref rid="fig1" ref-type="fig">figure 1</xref>
). The contributing hospitals all had existing suppliers and continued to use these suppliers during the study. Each participant gave written informed consent before enrolment and the study was approved by the relevant ethics committees and national and local research governance authorities.</p><sec id="cesec40"><title>Randomisation and masking</title>
<p>Between Dec 18, 2006, and Feb 16, 2009, after a surgical procedure aiming to debulk the disease, 1528 women were recruited at 263 centres in 11 countries (Australia, Canada, Denmark, Germany, Spain, Finland, France, UK, Norway, New Zealand, and Sweden) and randomly allocated (1:1) by a computer program to standard chemotherapy (standard chemotherapy group) or standard chemotherapy plus bevacizumab (bevacizumab group) in the order they were enrolled by block randomisation, stratifying for the following factors: FIGO stage (stage I–III with residual disease ≤1 cm, stage I–III with residual disease >1 cm, FIGO stage IV), intent to start chemotherapy 4 weeks or fewer after surgery versus intent to start chemotherapy more than 4 weeks after surgery, and Gynecologic Cancer Intergroup group. <ext-link ext-link-type="uri" xlink:href="http://www.ctu.mrc.ac.uk/icon7/eligibility_criteria.asp">Inclusion and exclusion criteria</ext-link>
are listed on the study website. Treatment in the standard chemotherapy group was for 18 weeks and treatment in the bevacizumab group was for 54 weeks; group allocation was not masked.</p><sec sec-type="methods" id="cesec50"><title>Procedures</title>
<p>QoL data for the ICON7 QoL substudy were collected on paper by patient self-reporting. Patients completed the QoL questionnaires on their own without conferring with friends or relatives and always before the administration of treatment or medical consultation (eg, baseline questionnaires were completed on day 1 before randomisation), at timepoints defined by the <ext-link ext-link-type="uri" xlink:href="http://www.ctu.mrc.ac.uk/plugins/StudyDisplay/protocols/ICON7%20Protocol%20V%204.0%20%2015%20October%2009.pdf">protocol</ext-link>
during outpatient attendances (<xref rid="fig1" ref-type="fig">figure 1</xref>
). QoL data were not collected after disease progression, but a scheduled QoL data collection for all patients still alive at 3 years will be reported in the future.</p><p>The 58 items of the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire–ovarian cancer module (EORTC QLQ–OV28) and the EORTC QLQ–core 30 (C30) were used to measure QoL within the preceding 7 days.<xref rid="bib14 bib15" ref-type="bibr"><sup>14,15</sup>
</xref><xref rid="bib16" ref-type="bibr"><sup>16</sup>
</xref><p>The definition we used for minimum clinically important difference for the C30 scales was originally defined (until March 24, 2011) as a change of ten points for any C30 scale.<xref rid="bib17" ref-type="bibr"><sup>17</sup>
</xref><xref rid="bib18" ref-type="bibr"><sup>18</sup>
</xref><xref rid="bib19" ref-type="bibr"><sup>19</sup>
</xref><p>The primary QoL endpoint was the global QoL score at 54 weeks on the C30 (range 0–100, with 100 being best QoL).<xref rid="bib15" ref-type="bibr"><sup>15</sup>
</xref><xref rid="fig1" ref-type="fig">figure 1</xref>
).</p><p>Our early hypothesis, after the first post-baseline assessment, was that, because angiogenesis is related to ascites formation,<xref rid="bib20" ref-type="bibr"><sup>20</sup>
</xref><p>Our mid hypothesis, halfway through the chemotherapy phase, at week 9, was that the administration of bevacizumab would slow wound healing<xref rid="bib21" ref-type="bibr"><sup>21</sup>
</xref><p>Our late hypothesis, from the end of the chemotherapy phase to 54 weeks, was that the continuation of treatment in the bevacizumab group would prolong an impairment of social functioning and increase fatigue.<xref rid="bib22" ref-type="bibr"><sup>22</sup>
</xref><p>We also did a sensitivity analysis to examine the effect of missing data. We collected data regarding compliance with questionnaire responses; when a form was missing, researchers recorded whether this was because the patient refused to complete the form, the centre was unable to complete the form (eg, staff absence), the patient's language needs were not met, the site missed the administration, or the patient was too ill.</p>
</sec><sec id="cesec60"><title>Statistical analysis</title>
<p>The sample size for ICON7 was calculated to provide 83% power to detect a 28% change in progression-free survival at 18 months of follow-up and 80% power to identify a 19% improvement in overall survival, each with a two-sided significance level of 5%, allowing for up to 5% non-compliance with protocol.</p>
<p>We compared differences between treatment groups in the primary QoL endpoint using ANOVA adjusting for baseline score against a two-sided statistical significance level of 0·05. Secondary QoL endpoints were analysed against a two-sided statistical significance level of p=0·05. Differences between the treatment groups in all other validated subscales were assessed against a two-sided significance level of p=0·01.</p>
<p>After primary analyses of all available data from both groups, we used imputation to characterise the potential effect of missing data. Where data were missing because of administration error at the site, we imputed average global QoL baseline scores for the group, inferring these data were missing at random. Data missing because of patient refusal or illness or missing without explanation were imputed as a reduction in global QoL of 15 points from the mean for that treatment group. Where data were missing because of death we imputed a global QoL of 0. Because of the higher number of women returning QoL data in the bevacizumab group than in the standard chemotherapy group (because time to disease progression was longer), we modelled the potential effect of data that were not sought because of disease progression by imputatation and comparison of a full range of values, examination of the effect of that imputation, and comparison with data within the Medical Research Council (MRC) ICON4 trial of QoL at first relapse in ovarian cancer, to calculate the range of clinically plausible values.<xref rid="bib8" ref-type="bibr"><sup>8</sup>
</xref><p>All analyses were undertaken on the intention-to-treat population using Stata version 10 or later.</p>
<p>This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375, and with EudraCT, number 2005-003929-22.</p>
</sec><sec id="cesec70"><title>Role of the funding source</title>
<p>The sponsor and funding sources had a role in the study through membership of a professional academic steering group. Roche had a role in study design, data interpretation, and writing of the report, through representation on the steering group for quality of life. The National Institute for Health Research through the UK National Cancer Research Network had a role in study design via peer review. The MRC as sponsor had a regulatory role, but their staff had a role in study design, data collection, data analysis, data interpretation, and writing of the report. ES was the sole representative of Roche on the steering group for the quality of life and was involved in the study design, data collection, data analysis, data interpretation, writing of the report, and the decision to submit for publication along with DS, MN, LE, MS, FH, JB, AL, GV, WQ, and AMS. DS, MN, WQ, and AMS had access to the raw QoL data. DS had full access to all of the data and the final responsibility for the decision to submit for publication.</p>
</sec><sec sec-type="results" id="cesec80"><title>Results</title>
<p>All 1528 women (764 in both the standard chemotherapy and the bevacizumab groups) enrolled in ICON7 were asked to provide data on QoL. <xref rid="tbl1" ref-type="table">Table 1</xref>
shows concordance with data collection by group. At baseline, 684 (90%) women in the standard chemotherapy group and 691 (90%) in the bevacizumab group provided complete data. By 54 weeks, 388 (51%) women in the standard chemotherapy group and 502 (66%) in the bevacizumab group had provided data; 254 (33%) women who received standard chemotherapy and 147 (19%) in the bevacizumab group had either progressive disease or had died (so no QoL data were sought), with an imbalance between the two groups (<xref rid="tbl1" ref-type="table">table 1</xref>
), and QoL data were missing for 122 (16%) women in the standard group and 115 (15%) of those in the bevacizumab group. Specific reasons for these missing data forms were given for 101 women (6·6%; 50 [6·5%] in the standard chemotherapy group and 51 [6·7%] in the bevacizumab group). For 85 of 101 forms (44 in the standard chemotherapy group and 41 in the bevacizumab group) the reason was centre administrative oversight, but for 15 (six in the standard chemotherapy group and nine in the bevacizumab group) it was because of either a patient declining to complete the form or illness. One patient in the bevacizumab group did not complete a data form because they were on holiday.</p><p>During the 18-week period of chemotherapy treatment in both groups, mean global QoL for women with data from both baseline and week 18 (333 women in the standard chemotherapy group and 444 women in the bevacizumab group) improved by 7·2 points (SD 24·4). A difference between the group mean global QoL scores of 5·1 points (95% CI 2·9–7·4) was noted at the end of chemotherapy when analysed for all women with available data (<xref rid="tbl2" ref-type="table">table 2</xref>
). The primary outcome, mean global QoL at 54 weeks, was better for women in the standard chemotherapy group (76·1 points [SD 18·2]) than for those in the bevacizumab group (69·7 points [19·1]). This difference, 6·4 points (95% CI 3·7–9·0), is clinically small by modern criteria<xref rid="bib18" ref-type="bibr"><sup>18</sup>
</xref><p>Analysis of our a-priori hypotheses did not support a difference between groups during the chemotherapy course in gastrointestinal problems or problems related to the surgical scar (<xref rid="tbl3" ref-type="table">table 3</xref>
). In the continuation bevacizumab phase, we did not note a difference between groups in the trajectory of social functioning or fatigue (<xref rid="tbl3" ref-type="table">table 3</xref>
).</p><p><xref rid="tbl4" ref-type="table">Table 4</xref>
shows data from the exploratory analysis of other subscales in the C30 and OV28 instruments. All differences were in favour of the standard chemotherapy group. Bevacizumab was associated with clinically small but statistically significant decrements of role functioning, financial worries, attitudes to disease or treatment, hormonal symptoms, and rash (all p<0·01).</p><p>After imputation of global QoL of 0 for patients who had died, we imputed a range of mean global QoL decrements (as estimates of the effect of progressive disease upon global QoL). Imputing a decrement of at least a 20-point reduction in global QoL for the effect of relapse of the cancer did not alter our findings of a statistically significant, clinically small, deficit in QoL for the bevacizumab group (<xref rid="fig2" ref-type="fig">figure 2</xref>
). If the decrement in global QoL from disease progression is imputed as a 30–50-point reduction then there is no statistically significant difference between the groups. If the decrement is imputed as a 60–70-point reduction, then the analyses favour the bevacizumab group. A clinically plausible estimate of global QoL in relapsed ovarian cancer was made from the ICON4 trial (unpublished, Medical Research Council Clinical Trials Unit, London, UK). The mean global QoL (using the C30) for women being treated for ovarian cancer at first relapse in ICON4 was 61 points compared with a baseline global QoL in ICON7 of 57 points.</p><sec sec-type="discussion" id="cesec90"><title>Discussion</title>
<p>We present findings from detailed QoL analyses from the ICON7 study of the role of bevacizumab in the first-line treatment of epithelial ovarian cancer. Global QoL at 54 weeks was better for women receiving standard chemotherapy than for those receiving standard chemotherapy plus bevacizumab. The difference between groups was clinically small by modern criteria<xref rid="bib18" ref-type="bibr"><sup>18</sup>
</xref><xref rid="box1" ref-type="boxed-text">panel</xref>
).</p><p>What the mechanism of a small decrement in QoL associated with bevacizumab might be remains unclear. We planned at study inception to examine whether bevacizumab seemed to improve the resolution of ascites, to cause a decrement to healing of abdominal wall wounds, or to prolong the disruption in day-to-day life associated with continuation of bevacizumab. None of those effects were noted. The decrease in QoL might be because of toxicity of bevacizumab, such as rash, hormonal symptoms, or the bleeding, thromboembolic or gastrointestinal perforations reported in toxicity data.<xref rid="bib4" ref-type="bibr"><sup>4</sup>
</xref><xref rid="bib4" ref-type="bibr"><sup>4</sup>
</xref><p>Alongside our results, the findings of the related Gynecologic Oncology Group (GOG) 218 study<xref rid="bib24" ref-type="bibr"><sup>24</sup>
</xref><xref rid="bib22" ref-type="bibr"><sup>22</sup>
</xref><p>Our study has some strengths. We studied a large sample, representative of the population of women making choices about postsurgical systemic treatment for ovarian cancer, enrolled at 263 international centres, with 10% having high-risk FIGO early stage disease but 70% stage IIIC or IV disease and one quarter having more than 1·0 cm of residual disease after surgical debulking.<xref rid="bib4" ref-type="bibr"><sup>4</sup>
</xref><p>However, some study weaknesses should be considered. Our assessment did not include direct data on the women's experience beyond cancer progression. We decided to measure QoL in this way because of issues of patient burden, incomplete data on treatment after relapse, and study cost. The amount of missing data beyond disease progression was not balanced between the groups. Sensitivity analyses were undertaken to examine this issue, using mean imputation for missing data (rather than multivariate imputation taking into account potentially influential factors such as age and stage) at baseline and later, and imputation of clinically plausible QoL after progressive disease from other related trials do not alter our conclusions. ICON7 is an open-label study, which could affect QoL, although it also represents a realistic comparison of treatments with and without the addition of bevacizumab to standard chemotherapy. Based on animal models, there has been debate over the effect of antiangiogenic drugs on cancer invasiveness after resistance has developed.<xref rid="bib25" ref-type="bibr"><sup>25</sup>
</xref><xref rid="bib26 bib27" ref-type="bibr"><sup>26,27</sup>
</xref><p>The addition of bevacizumab to standard combination chemotherapy in ovarian cancer prolonged progression-free survival. However, QoL seems to be impaired to a clinically small extent during bevacizumab continuation treatment, with no direct evidence that this was because of the specific hypotheses we studied. In future, as further drugs are developed with continuation schedules, the effect on QoL outcomes that are directly reported by patients will be an important consideration alongside improvements in the duration of cancer control.</p>
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</sec><ack><title>Contributors</title>
<p>DS, MN, LE, MS, FH, JB, AL, GV, ES, WQ, and AMS designed the study, analysed and interpreted data, and wrote the manuscript. EP-L, GK, AC, JP, MSC, PB, AO, and TP designed the study, collected and interpreted data, and wrote the manuscript.</p>
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<p>EP-L received honoraria from Roche. GK, FH, and AC have acted on advisory boards for Roche. AC has also received honoraria and research grants from Roche. AL and GV are EORTC Quality of Life Group members. EORTC instruments were used in this trial upon payment of a fee, which is invested by the group in future quality-of-life research; however, AL and GV did not receive any financial reward. ES is an International Payer Strategy Leader (health economics outcomes research/patient-reported outcomes research) for Roche. JP has received research funding from Roche. PB has acted on advisory boards and received travel grants from Roche. AO has received research funding for clinical trials from Roche. TP has acted on advisory boards for Roche. DS, MN, LE, MS, JB, MSC, WQ, and AMS declare that they have no conflicts of interest.</p>
</ack><floats-group><fig id="fig1"><label>Figure 1</label>
<caption><p>Study schema, with measurement of quality of life over time and timing of a-priori quality-of-life outcomes</p>
<p>Every coloured box in the top panel represents one 3-week chemotherapy cycle. FIGO=International Federation of Gynecology and Obstetrics.</p>
</caption><graphic xlink:href="gr1"></graphic>
</fig><fig id="fig2"><label>Figure 2</label>
<caption><p>Sensitivity analyses</p>
<p>The figure shows point estimates with 95% CIs for the difference between the treatment groups (bevacizumab group mean minus standard chemotherapy group mean) after imputing a range of post-progression global quality-of-life values to estimate the potential effect of missing data. Values above the dashed line favour bevacizumab; those below the dashed line favour standard chemotherapy. *No imputation.</p>
</caption><graphic xlink:href="gr2"></graphic>
</fig><table-wrap id="tbl1" position="float"><label>Table 1</label>
<caption><p>Attrition in returns of health-related quality-of-life data</p>
</caption><table frame="hsides" rules="groups"><thead><tr><th></th>
<th colspan="4" align="left"><bold>Standard chemotherapy group (n=764)</bold>
<hr></hr>
</th><th colspan="4" align="left"><bold>Bevacizumab group (n=764)</bold>
<hr></hr>
</th><tr><th></th>
<th align="left">n (%)</th>
<th align="left">Died (%)</th>
<th align="left">Progression but alive (%)</th>
<th align="left">No data (%)</th>
<th align="left">n (%)</th>
<th align="left">Died (%)</th>
<th align="left">Progression but alive (%)</th>
<th align="left">No data (%)</th>
</tr><tbody><tr><td align="left">Screening</td>
<td align="left">684 (90%)</td>
<td align="left">0 (0%)</td>
<td align="left">0 (0%)</td>
<td align="left">80 (10%)</td>
<td align="left">691 (90%)</td>
<td align="left">0 (0%)</td>
<td align="left">0 (0%)</td>
<td align="left">73 (10%)</td>
</tr><tr><td align="left">Week 18</td>
<td align="left">662 (87%)</td>
<td align="left">11 (1%)</td>
<td align="left">15 (2%)</td>
<td align="left">76 (10%)</td>
<td align="left">693 (91%)</td>
<td align="left">7 (1%)</td>
<td align="left">5 (1%)</td>
<td align="left">59 (8%)</td>
</tr><tr><td align="left">Week 54</td>
<td align="left">388 (51%)</td>
<td align="left">71 (9%)</td>
<td align="left">183 (24%)</td>
<td align="left">122 (16%)</td>
<td align="left">502 (66%)</td>
<td align="left">43 (6%)</td>
<td align="left">104 (14%)</td>
<td align="left">115 (15%)</td>
</tr><table-wrap-foot><fn><p>No imbalance of attrition was observed, comparing study groups by age, centre, country, or stage (data not shown).</p>
</fn><table-wrap id="tbl2" position="float"><label>Table 2</label>
<caption><p>Mean global quality-of-life score between groups at key timepoints for all patients with available data</p>
</caption><table frame="hsides" rules="groups"><thead><tr><th></th>
<th align="left"><bold>Standard chemotherapy group</bold>
</th><th align="left"><bold>Bevacizumab group</bold>
</th><th align="left"><bold>Difference</bold>
</th><th align="left"><bold>p value</bold>
</th><tbody><tr><td align="left">Baseline (before randomisation)</td>
<td align="left">58·6 (20·6)</td>
<td align="left">55·1 (20·8)</td>
<td></td>
<td></td>
</tr><tr><td align="left">Week 18 (end of chemotherapy)</td>
<td align="left">64·4 (20·3)</td>
<td align="left">59·2 (19·4)</td>
<td align="left">−5·1 (−7·4 to −2·9)</td>
<td align="left"><0·0001</td>
</tr><tr><td align="left">Week 54 (end of continuation bevacizumab)</td>
<td align="left">76·1 (18·2)</td>
<td align="left">69·7 (19·1)</td>
<td align="left">−6·4 (−9·0 to −3·7)</td>
<td align="left"><0·0001</td>
</tr><table-wrap-foot><fn><p>Data are mean (SD) or difference (95% CI). Numbers of patients per group are shown in <xref rid="tbl1" ref-type="table">table 1</xref>
. p values calculated by ANOVA controlled for baseline value.</p><table-wrap id="tbl3" position="float"><label>Table 3</label>
<caption><p>Analyses of three quality-of-life hypotheses</p>
</caption><table frame="hsides" rules="groups"><thead><tr><th></th>
<th colspan="2" align="left"><bold>Mean score</bold>
<hr></hr>
</th><th align="left"><bold>Difference (95% CI)</bold>
</th><th align="left"><bold>p value</bold>
</th><tr><th></th>
<th align="left">Standard chemotherapy group</th>
<th align="left">Bevacizumab group</th>
<th></th>
<th></th>
</tr><tbody><tr><td colspan="5" align="left"><bold>Early: resolution of ascites</bold>
</td><tr><td align="left">Gastrointestinal symptoms</td>
<td align="left">76·4 (n=566)</td>
<td align="left">74·7 (n=606)</td>
<td align="left">−1·6 (−3·5 to 0·2)</td>
<td align="left">0·43</td>
</tr><tr><td colspan="5" align="left"><bold>Mid: scar symptoms</bold>
</td><tr><td align="left">Pain</td>
<td align="left">22·0 (n=596)</td>
<td align="left">22·7 (n=628)</td>
<td align="left">0·7 (−2·0 to 3·4)</td>
<td align="left">0·65</td>
</tr><tr><td align="left">Physical functioning</td>
<td align="left">80·5 (n=594)</td>
<td align="left">78·8 (n=624)</td>
<td align="left">−1·6 (−3·7 to 0·5)</td>
<td align="left">0·18</td>
</tr><tr><td align="left">Social functioning</td>
<td align="left">70·6 (n=584)</td>
<td align="left">70·2 (n=621)</td>
<td align="left">−0·4 (−3·4 to 2·5)</td>
<td align="left">0·61</td>
</tr><tr><td align="left">Body image</td>
<td align="left">36·2 (n=586)</td>
<td align="left">35·4 (n=609)</td>
<td align="left">−0·9 (−4·2 to 2·4)</td>
<td align="left">0·62</td>
</tr><tr><td colspan="5" align="left"><bold>Late: social functioning and fatigue</bold>
</td><tr><td align="left">Social functioning</td>
<td align="left">13·7 (n=319)</td>
<td align="left">11·9 (n=430)</td>
<td align="left">−1·8 (−5·1 to 1·6)</td>
<td align="left">0·30</td>
</tr><tr><td align="left">Fatigue</td>
<td align="left">−15·8 (n=324)</td>
<td align="left">−14·9 (n=435)</td>
<td align="left">0·9 (−2·3 to 4·1)</td>
<td align="left">0·58</td>
</tr><table-wrap-foot><fn><p>p values calculated by ANOVA controlled for baseline value.</p>
</fn><table-wrap id="tbl4" position="float"><label>Table 4</label>
<caption><p>Exploratory analyses of quality-of-life subscales</p>
</caption><table frame="hsides" rules="groups"><thead><tr><th></th>
<th colspan="3" align="left"><bold>Mean score at week 54</bold>
<hr></hr>
</th><th align="left"><bold>p value</bold>
</th><th align="left"><bold>Combined SD</bold>
</th><th align="left"><bold>Effect size</bold>
</th><tr><th></th>
<th align="left">Standard chemotherapy group</th>
<th align="left">Bevacizumab group</th>
<th align="left">Difference (95% CI)</th>
<th></th>
<th></th>
<th></th>
</tr><tbody><tr><td colspan="7" align="left"><bold>EORTC QLQ-C30</bold>
</td><tr><td align="left">Role functioning</td>
<td align="left">84·5 (n=332)</td>
<td align="left">75·6 (n=438)</td>
<td align="left">−8·9 (−12·3 to 5·5)</td>
<td align="left"><0·0001</td>
<td align="left">24·4</td>
<td align="left">Small<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td align="left">Cognitive functioning</td>
<td align="left">84·9 (n=335)</td>
<td align="left">81·4 (n=445)</td>
<td align="left">−3·5 (−6·5 to 0·4)</td>
<td align="left">0·033</td>
<td align="left">21·6</td>
<td align="left">Small<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td align="left">Emotional functioning</td>
<td align="left">77·5 (n=335)</td>
<td align="left">75·4 (n=446)</td>
<td align="left">−2·1 (−5·4 to 1·2)</td>
<td align="left">0·21</td>
<td align="left">23·2</td>
<td align="left">Trivial<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td align="left">Nausea and vomiting</td>
<td align="left">2·6 (n=334)</td>
<td align="left">3·7 (n=444)</td>
<td align="left">1·0 (−0·3 to 2·4)</td>
<td align="left">0·12</td>
<td align="left">9·5</td>
<td align="left">Trivial<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td align="left">Dyspnoea</td>
<td align="left">11·8 (n=339)</td>
<td align="left">14·8 (n=436)</td>
<td align="left">3·0 (−0·1 to 6·1)</td>
<td align="left">0·10</td>
<td align="left">21·7</td>
<td align="left">Trivial<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td align="left">Appetite loss</td>
<td align="left">4·2 (n=333)</td>
<td align="left">7·6 (n=439)</td>
<td align="left">3·4 (1·1 to 5·7)</td>
<td align="left">0·0035</td>
<td align="left">16·2</td>
<td align="left">Trivial<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td align="left">Finance</td>
<td align="left">12·8 (n=330)</td>
<td align="left">18·9 (n=440)</td>
<td align="left">6·1 (2·2 to 9·8)</td>
<td align="left">0·0072</td>
<td align="left">26·7</td>
<td align="left">Small<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td align="left">Diarrhoea</td>
<td align="left">5·0 (n=332)</td>
<td align="left">7·3 (n=440)</td>
<td align="left">2·3 (0·1 to 4·5)</td>
<td align="left">0·037</td>
<td align="left">15·5</td>
<td align="left">Trivial<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td align="left">Sleep</td>
<td align="left">24·4 (n=333)</td>
<td align="left">28·6 (n=443)</td>
<td align="left">4·2 (0·1 to 8·3)</td>
<td align="left">0·078</td>
<td align="left">28·8</td>
<td align="left">Small<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td align="left">Constipation</td>
<td align="left">13·0 (n=335)</td>
<td align="left">15·8 (n=442)</td>
<td align="left">2·7 (−0·8 to 6·2)</td>
<td align="left">0·14</td>
<td align="left">24·6</td>
<td align="left">Trivial<xref rid="tbl4fn1" ref-type="table-fn">*</xref>
</td><tr><td colspan="7" align="left"><bold>EORTC QLQ-OV28</bold>
</td><tr><td align="left">Attitude</td>
<td align="left">27·6 (n=329)</td>
<td align="left">33·3 (n=443)</td>
<td align="left">5·7 (2·0 to 9·3)</td>
<td align="left">0·0029</td>
<td align="left">25·7</td>
<td align="left"><xref rid="tbl4fn2" ref-type="table-fn">†</xref><tr><td align="left">Peripheral neuropathy</td>
<td align="left">6·3 (n=320)</td>
<td align="left">9·3 (n=423)</td>
<td align="left">3·0 (0·3 to 5·8)</td>
<td align="left">0·052</td>
<td align="left">19·0</td>
<td align="left"><xref rid="tbl4fn2" ref-type="table-fn">†</xref><tr><td align="left">Hormonal</td>
<td align="left">13·0 (n=326)</td>
<td align="left">17·3 (n=436)</td>
<td align="left">4·3 (1·6 to 7·0)</td>
<td align="left">0·0042</td>
<td align="left">18·8</td>
<td align="left"><xref rid="tbl4fn2" ref-type="table-fn">†</xref><tr><td align="left">Rash</td>
<td align="left">12·4 (n=326)</td>
<td align="left">18·0 (n=433)</td>
<td align="left">5·6 (2·3 to 8·9)</td>
<td align="left">0·0010</td>
<td align="left">23·1</td>
<td align="left"><xref rid="tbl4fn2" ref-type="table-fn">†</xref><table-wrap-foot><fn><p>p values calculated by ANOVA controlled for baseline value. n=number of women who responded to the individual questionnaire items in question at that point in time. EORTC QLQ–C30=European Organisation for Research and Treatment of Cancer quality-of-life questionnaire–core 30. EORTC QLQ–OV28=EORTC QLQ–ovarian cancer module.</p>
</fn><table-wrap-foot><fn id="tbl4fn1"><label>*</label>
<p>According to Cocks and colleagues.<xref rid="bib18" ref-type="bibr"><sup>18</sup>
</xref><table-wrap-foot><fn id="tbl4fn2"><label>†</label>
<p>According to Cohen.<xref rid="bib19" ref-type="bibr"><sup>19</sup>
</xref>
